Developing a RiskMAP

Louis A. Morris, Ph.D.FDA Regulatory Symposium

August 25, 2005

Challenge

Testing Approval Product Adoption I II III Intro Growth Maturity Decline

B

What can we do in Phase I-III to assure A and avoid B and C?

Inception

A

Approval

TIME

SALES

C

Significant Withdrawals• Seldane (terfenadine) 2/98• Posicor (mibefradil) 6/98• Duract (bromphenac) 6/98• Hismanal (astemizole) 6/99• Roxar (grepafloxacin) 11/99• Propulsid (cisapride) 3/00• Rezulin (troglitazone) 3/00• Lotronex (alosetron HCl)* 8/00• Raplon (rapcuronium) 3/01• Baycol (cerivaxtatin) 8/01• Vioxx (rofecoxib) 9/04• Tysabri (natalizumab)** 2/05

* Reintroduced, ** Marketing temporarily halted

And in Recent Months• Asthma Drugs Okayed to stay on market 7/05• Palladone withdrawn 7/05• ED Drug labeling (blindness: “we 7/05

do not know if drugs” cause condition)• Antidepressants (black box, suicidality) 6/05• Duragesic black box added 6/05• Natrecor (heart-failure drug) restricted

to “acutely sick hospital patients” 6/05• Iressa sales restricted to those who 6/05

already take it and are benefiting • ADHD Drug labeling (add: suicidal 6/05

thoughts and hallucinations)• NSAIDS (labeling, withdrawal of Bextra) 4/05

Objectives

• The New Era of Risk Management– FDA and Product Liability

• FDA Draft Guidance: RiskMAP– When will a RiskMAP be needed?

• Selected drugs– What will be required for a RiskMAP?– How do I design a RiskMAP for my drug?

• Conclusions

FDA’s Refined Concepts

•• Risk Management:Risk Management: “The overall and “The overall and continuing process of minimizing risks continuing process of minimizing risks

throughout a product’s lifecycle to throughout a product’s lifecycle to optimize its benefit/risk balance.”optimize its benefit/risk balance.”

•• Developing Interventions to prevent harm:Developing Interventions to prevent harm:Risk Minimization Action Plan (RiskMAP)

RiskMAP• A strategic safety program

– designed to minimize known product risks while preserving its benefits.

• One or more safety goals and related objectives • Uses one or more interventions or “tools”

– extend beyond the package insert and routine post marketing surveillance.

• Guidance describes:– conditions stimulating the need for a RiskMAP,– the selection of tools,– the format for RiskMAPs, and– the evaluation processes necessary to develop and to

monitory the success of a risk minimization plan.

When is a RiskMAP Needed?• FDA

– the nature of risks verses benefits• risk tolerance issues such as population affected, alternative therapy available

and reversibility of adverse events– preventability of the adverse event, and – probability of benefit or success of the risk minimization interventions

• Likely Candidates– Drugs that have serious or life threatening contraindications, warnings,

precautions or adverse effects – When patient/professional behaviors can mitigate risks

• such as pregnancy prevention, blood tests, overdose/misuse avoidance, awareness and action related to specific safety signals

– When people other than the patient may be at risk • Such as, a child may use the product inadvertently

– Schedule II drugs• Singled out by FDA, with concerns for misuse, abuse, addiction, diversion and

overdose as likely candidates for a RiskMAP.

Look for Benchmarks, Narrow R/B Tolerances, Preventability, Signals

However, many drugs have educational interventions to minimize risks – what is the level of RM needed?

Examples of Drugs with RM Distribution Controls

• Accutane (isotretinoin) - severe recalcitrant nodular acne • Actiq (fentanyl citrate) - severe cancer pain • Clozaril (clozapine) - severe schizophrenia• Lotronex (alosetron

hydrochloride) - severe irritable bowel syndrome in women • Mifiprex (mifepristone

or RU-486) - termination of early intrauterine pregnancy • Thalomid (thalidomide) - erythema nodosum leprosum • Tikosyn (dofetilide) - maintenance of normal sinus rhythm • Tracleer (bosentan) - severe pulmonary arterial hypertension • Trovan (trovafloxacin

mesylate or alatrofloxacin mesylate injection) - severe, life-threatening infections

• Xyrem (sodium oxybate) - narcolepsy

• Who should not take “Drug”?– Absolute Contraindications, lab test values, pregnancy status, etc.

• How should I take “Drug”?– Timing, delivery system, unique condition

• What should I avoid while taking “Drug”?– Other meds, foods, activities

• What are the possible or reasonably likely side effects?– Unavoidable, rare but serious

Practical Guide

Four Medication Guide Questions

Contraindication

Usage Directions

Avoidance Behavior

Consent

Designing a RiskMAP (1)

• Must clearly specify risk to be managed – Use PI (or target profile) to select and specify problems

to be addressed– Organize and focus on problems needing RiskMAP

• Understand the “System”– Processes underlying drug prescribing, distribution and

use– Use Root Cause or FMEA analysis to specify sources

of system failures

Correctly “framing the problem” points to the best solution

System AnalysisMedication Dispensing

Retrieves Name

WritesPrescription

Patient Delivery

RPhInterpret

MDDiagnosis

Retrieve Drugfrom Shelf

DispensesMedicine

Error Error

ErrorErrorError

Error

Error

Failure Mode and Effects Analysis

• Develop System Steps (or subsystem)– Sources of Failure for each step– Probability– Severity– Likelihood Of Detection– Develop index by multiplication

Set Goals and Objectives

• Plan must specify – overall goals of the RiskMAP

• the desired endpoints for safe product use.

• The objectives for each goal– must be specific and measurable. – specify the behaviors and processes necessary for the

stated goals to be achieved. • For example, if our goal is to prevent pregnancy, then an

objective may be that all women must have a negative pregnancy test performed within seven days of initiating therapy.

Designing a RiskMAP (2)

• Develop a behaviorally predictive model– the set of beliefs underlying behavioral

intentions, – the motivations that support or stand in the way

of exhibiting desired behavior and – the environmental conditions that facilitate or

place barriers to compliance.

What do you want people to do?

Behavioral Models

• Attitude Change– Understanding Beliefs and Persuasion

• Improving Involvement (personal relevance) or Competency (self-efficacy)

• Decision making (mental models)– Think and act like experts

• Field Theory (barriers and facilitators)• Stages of Change or Precaution Adoption• Emotional Models (fear appeals or positive affect)

Choose the Model that best fits the problem

Designing a RiskMAP (3)

• Developing Interventions– Selecting Tools– FDA three classes are descriptive but not predictive– Suggest two class categorization

• Informational Tools– Use Communication Model to select tools

• Distribution Controls– Additional classes of tools available

• Economic Controls (incentives for compliance)’• Product Modifications (reformulations, system delivery)• Combinations and systems improvements

Personal view: Tools fit the 4 Ps of Marketing

Tools: FDA Categorization• “Targeted education or outreach.”

– health care professionals (e.g., letters; training programs; letters to the editor). – promotional techniques to publicize risk management (e.g., advertisements and

sales representatives’ distribution of information). – consumers and patients (e.g., Medication Guides and patient package inserts,

limiting sampling or direct-to-consumer advertising)• “Reminder systems.”

– training or certification programs, physician attestation, patient agreements), specialized packaging limiting the amount of medication dispensed

• “Performance-Linked Access Systems.”– acknowledgment, certification, enrollment, or records– Limiting prescribing to certified health care practitioners, – limiting dispensing to certified pharmacies or practitioners – Limiting access to patients with evidence of fulfilling certain conditions (e.g.,

negative laboratory test results).

Not particularly helpful for planning…Exanta review, FDA pointed to lack of Reminder and Performance Systems

Tools Selection (FDA)

• Necessary And Sufficient for Influencing Behavior

• FDA: Selecting Tools– Input from stakeholders– Consistency with existing tools– Documented evidence– Degree of validity and reproducibility

Needed: A Rationale Communications Model

Approach to Developing Program

• Check list (bottom up):– Review what others have done and copy– Modify as needed

• Program Design (top down):– Develop Goals and Objectives– Select Tools to meet Goals and Objectives– Plan Evaluation

Suggest do top down and then bottom up: as a reality check

Behavioral MaintenanceTelephoneRecurring Interventions (telephone calls)

Persuasion or EmotionPhysician or Starter KitVideo Tape or CDChoice of TherapyPhysicianDecision Aid

Behavioral CommitmentPhysicianPatient Agreement or Contract

Reminder or time sensitive control message

Medication Vial or Prescription

Stickers: Medication Vial or Prescription

ReminderStarter KitWallet CardRisk “signal”/compliancePackageWarning on PackageAcknowledgement of RisksPhysicianInformed Consent

Risk Communication and Methods of Hazard Avoidance

PackageMedication GuideRisk CommunicationPackage/ RPhPPI

General EducationPhysicianBrochurePurpose (strength)DistributionInfo. Tools

Communications Process

• Exposure Distribution• Attention Readership• Interest Willingness to Read• Understand Comprehension• Accept Attitude Change• Memory Recall/Recognition Tests• Decide Decision Making Scenarios • Behave Intention to Heed/Behavior• Learn Behavior Maintenance

Goal/Barrier Measure

Select Vehicles to Maximize Communication Goal May need a combination of Vehicles

Sample Tactics Matrix

Materials with logoBrochure/Web site, MD materials

Waiting room placard, pharmacy printouts

Patients/Partners

PosterGrand Rounds Training

Sales force materials

ER

Desktop Media, posterSales Rep MaterialMailingMDs

Desktop MediaTraining videoAffirmative Scripts, Q&As

CRM

Leave behindsTraining manualDetail AidSales

ReinforcementMotivationAwarenessGoalAudience

Theme: Risk Avoidance Involvement Logo as ReminderTheme: Risk Avoidance Involvement Logo as Reminder

Distributional Controls

Closed System

Prior Approvals

CertificationSpecial Packaging

Record Keeping

Controlled Substances

Actiq Fosamax

Tikosyn Thalomid Accutane

Clozaril

Varying Levels of Control

Actiq Packaging

Tikosyn

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on dofetilide should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION. TIKOSYN is available only to hospitals and prescribers who have received appropriate TIKOSYN dosing and treatment initiation education

Results The recommended starting dose was prescribed more frequently in the dofetilide group than in the sotalol group (79% vs 35%,). A higher number of patients in the dofetilide group received the recommended baseline tests for potassium (100% vs 82%), magnesium (89% vs 38%), serum creatinine (100% vs 82%), and electrocardiography (94% vs 67%,). A significantly greater proportion of patients in the dofetilide group received recommended electrocardiograms obtained after the first dose and subsequent doses Conclusion Better adherence to several dosing and monitoring recommendations in the dofetilide group may be caused by the presence of the risk-management program. However, low usage of dofetilide during the study period may signify an unintended, negative consequence of the risk-management program.

Tikosyn Evaluation

Accutane RMP• Accutane Approved 1982

• Pregnancy Category X, Patient Brochure

Pregnancy Prevention Program, 1998Warning Labels, Informed Consent, Kit for Prescribers, Tracking Study to Assess Use of Kit, Patient Enroll ment Survey,

SMART Program October 2001Enhanced Education, Physician Qualification, Yellow Stickers, Two Pregnancy Tests Prior to First Rx, Mandatory Pregnancy Testing Before Each Rx, Medication Guide, Two Forms of BC, 30-day Supply, No Refills, Develop Back-up Program for Mandatory Registries

• FDA Called All Manufacturers December 2003Need to Modify RMP, Advisory Committee Meeting in February 2004Current Program being modified (males included, blood testing record, patient qualification test)

iPLEDGE Program August 2005isotrotenian

Pregnancy Case Reports:Pre-S.M.A.R.T. vs. S.M.A.R.T.®

8956Treatment initiation date unknown

9494Treatment initiation date known

183150Total number

S.M.A.R.T.®Pre-S.M.A.R.T.

Number of Rxs decreased, rate did not change

Evolution of Accutane RiskMAP

X XXLinking of Patient Ed./RM to Dispensing

XRegistration of Pharmacy

XRegistration of Patient

CentralizedDecentralizedDecentralizedPregnancy Reporting

X XXXContraceptive Counseling

X XXAuditing Mechanism

XXUse of Qualification Sticker

XXLimited to 30 Days Supply/No Refills

X XXLinking of Pregnancy Test to Dispensing

X XXAuthorized Prescriber Check Mechanism

X XX XXEducational Component

X XRegistration of Physician

iPLEDGES.M.A.R.TPPPProgram Features

Lotronex

Fears cited for IBS drug's lagging salesBy Rita Rubin, USA TODAYSales of Lotronex, a drug to treat irritable bowel syndrome thatwas temporarily taken off the market because of safety concerns,have been far lower than expected since its reintroduction in November 2002, its maker says.GlaxoSmithKline attributes Lotronex's disappointing sales to theRisk Management Program required by the Food and Drug Administration. The program, which is designed to reduce the risk of potentially life-threatening side effects, requires that doctors attest that they are qualified to prescribe Lotronex. Doctors and pharmacists also are supposed to give patients an FDA-approved Medication Guide before they start taking Lotronex.

Posted 5/5/2004 1:14 AM

Sales (TRx) Following Launch

Risk Management Irony

Perception of Risk

Willing-ness to

Use

Safety =BenefitsRisks

Beliefs Perceptions

Communications do more than inform, they modify modify beliefs, may change perceptions

The Comfort ZoneMD Perceptions:

Will benefit and Protect patient,Willing to try

Too little RM

Too Much RM

Comfort Zone

Personal Liability

Too much work to use

Drug may hurt patient

Too risky to try

1) extensive education of prescribers, pharmacists and patients on proper pain management and the safe use of OxyContin in appropriate patients.2) active surveillance to detect signals of abuse, diversion, addiction and overdose. The company's RADARS(R) System can detect signals down to the three digit zip code in specific geographic areas.3) a wide range of interventions, including support and education of law enforcement, targeted education of healthcare professionals on combating diversion and abuse, and awareness and prevention programs to the public in affected communities about the dangers of prescription drug abuse.

Oxycontin: MAADO

Misuse, Abuse, Addiction, Diversion and Overdose

Clozapine RMP

• Black Box WarningAgranulocytosis, Seizures, Myocarditis

• No Blood No Drug MonitoringRelaxation from QW to QOW

• Pharmacy Registry

• Patient Registry

• Physician Registry

Thalidomide RMP• S.T.E.P.S. Program Elements

Required Pregnancy Testing

Required Birth Control Measures

Physician Education

Patient Education

Registration

Patient Informed Consent Forms

Restricted Distribution System

Patented Program: Isotretinoin to License Procedures

Controlled Distribution

• MD always Controls Distribution • Additional Limitations by controlling

– Who prescribes, dispenses, uses– Conditions of Use

• MD with enhanced limitations• Necessary testing • Necessary knowledge qualifications• Necessary evaluation

Distribution Limitations

Must join registry

Consent or Agreement

Qual. check (knowledge self-admin)

No pre-existing condition

Patient

Controlled Access

AgreementSigned

Drug Admin-istratin

Limited to specialty pharmacy

Pharm-acy

Must use sticker

Letter of Under-standing

CE trainingLimited to medical specialty

MD

Manufacturer sets conditions

Self-At-testation

Additional Training

Existing Qualification

Mandatory vs. Voluntary Debate

System Enhancements

• Focus on Outcomes, not Process– Measure knowledge and provide feedback

where needed• Immediate: programmed learning• Personalized form to patient• Customized form to MD (patient experience model)

• Integration of safety assessment and risk minimization

DoctorDoctor

PatientPatientMultiplatform

Delivered Tests

MultiplatformDelivered

Tests

SafetyAssessment

SafetyAssessmentPeriodic

Periodic

MD or PatientRegisters

Patient

MD or PatientRegisters

Patient

Com

pilation & R

eportingC

ompilation &

Reporting

Patient Education& Feedback

Patient Education& Feedback

RM Evaluation

RM Evaluation

Patient Experience Feedback

Patient Experience Feedback

MD Intervention

MD Intervention

IterativeIterative

Multi-Function Registry

Multifunction Registry

• Survey Risk Knowledge, Attitudes, Intentions– Provide Individual Feedback to MD/Patient

• Survey to Evaluate RM Intervention– Combine data to evaluate Impact

• Measure Hypothesized ADEs in Registry• Survey forms carefully designed to avoid

question-asking biases

Create Specialized BenefitCreate Specialized Benefit--Risk DatabaseRisk Database

Black Box as a Signal

QUOTE OF THE DAY"Having a black box on the label is a big deal. It's pretty astounding to go from a year ago thinking this is one of the most benign drugs to a 180-degree turn in the opposite direction." Dr. Susan Hendrix, a gynecologist, on the government decision to require warning labels on drugs containing estrogen.

What can we do in the Drug Development Process to Plan for

Appropriate Use? (1)• Collect safety data, better identify and quantify

drug risks• Understand the Provider and User

– Assumptions, perceptions and beliefs– How the drug will be used in practice– Willingness to accept messages

• Test Interventions – Comprehension Testing of Messages and Tools– Include Program in Phase III Trials

What can we do in the Drug Development Process to Plan for

Appropriate Use? (2)• Develop rationale for plans/questions

(patient and provider surveys)• Validate Evaluation Questionnaires (e.g.,

patient knowledge, beliefs)• Develop initial registry (rollover to phase

IV)• Create advisory board – patients,

physicians

Continuous Quality Improvements

• Seek to avoid All or None Reactions– Add more/redesign tools if current ones not working

• Seek to “diagnose” cause for failures– Redesign interventions based on data

• Form Committees– Working Committee– Oversight and Review– Periodic Meetings

• Each 6 months

Benchmarking Success:

Seek to improve over time, avoid setting an a priori level

Conclusion

• FDA guidance is reasonable and responsive to public input

• Companies must begin to adapt their thinking to incorporate risk minimization– Ball is in pharma’s court – develop best practices, plan

for RM during drug development – FDA will design Risk Minimization Plans if

pharmaceutical companies do not• Still in a period of learning, not a lot of successes

– Innovation and evaluation is needed – Vioxx Fallout—look for more stringent reviews